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PURPOSE: The aim of this paper is to understand at a given temperature (1) the role of template films, the droplet volume of a saturated sulfathiazole aqueous solution and the solvent on polymorph screening of sulfathiazole on a silicon wafer, and (2) the effect of template films on the acetaminophen crystal face at the template-crystal interface. MATERIALS AND METHODS: Template Effect: Spun cast template films of non-annealed chitosan and annealed chitosan at 140 degrees C on silicon wafers were prepared. A 0.01-cm(3) saturated sulfathiazole aqueous solution droplets were deposited on both kinds of chitosan film. Sulfathiazole crystals were produced on those films by evaporation at 25 degrees C. Volume Effect: Different droplet volumes of a saturated sulfathiazole aqueous solution ranging from 0.01 to 0.14 to 2.7 cm(3) were deposited on non-annealed chitosan films. Sulfathiazole crystals were generated on those films by evaporation at 25 degrees C. Solvent Effect: 0.01 cm(3) saturated sulfathiazole methanol solution droplets were deposited on non-annealed chitosan films and sulfathiazole crystals were formed on those films by evaporation at 25 degrees C. The formation pathways of different sulfathiazole crystal polymorphs of the above mentioned effects were analyzed and verified by systematic studies. Template-crystal Interfacial Study: Millimeter-sized acetaminophen crystals were successfully grown on non-annealed chlorosulfonated poly(ethylene) (PE-Chl) and chitosan template films by cooling the saturated acetaminophen aqueous solution from 50 to 25 degrees C in which those template films were immersed. The bonding energies for specific carbons collected by electron spectroscopy for chemical analysis (ESCA) at the acetaminophen crystal surface, together with the molecular interactions between acetaminophen and PE-Chl and between acetaminophen and chitosan in separately prepared solid dispersion film samples detected by Fourier transformed infrared (FTIR) spectroscopy, proved to be useful for identifying the crystal face of acetaminophen essential for its specific intermolecular interactions at the template-crystal interface. RESULTS: Thermodynamically metastable sulfathiazole Form I crystals were reproducibly obtained on the non-annealed chitosan films whereas the stable sulfathiazole Form III crystals were repeatedly formed on the annealed chitosan films. Droplet volumes and solvents were also found responsible for the polymorphic outcome of sulfathiazole in the kinetically driven area of two overlapping metastable zones from two competing polymorphs of Form I and Form III. Thermodynamically stable sulfathiazole Form III crystals were formed on the non-annealed chitosan films instead when the droplet volumes of a saturated sulfathiazole aqueous solution were increased from 0.01 to 0.14 cm(3) and 2.7 cm(3). When the solvent was changed from water to methanol, the thermodynamically stable sulfathiazole Form III crystals were again observed on the non-annealed chitosan films even from the 0.01 cm(3) saturated sulfathiazole methanol solution droplets. CONCLUSIONS: Template surfaces were thought to provide specific functional groups to either change the energy barrier for the nuclei formation of the thermodynamically metastable Form I or alter the droplet contact angle and the droplet surface area which was related to the droplet evaporation time. The evaporation time determines the amount of time available for the polymorphic transformation from Form I to Form III. Apparently, droplet volumes could also determine the amount of time needed to reach supersaturation and the amount of time available for a polymorphic transformation from Form I to Form III. In addition, the molecular conformation and viscosity of solvents such as methanol might alter the original nucleation kinetics in water and lead to a more rapid polymorphic transformation from Form I to Form III. Template films of PE-Chl and chitosan were found to be critical for determining the face of a millimeter-sized acetaminophen crystal at the template-crystal interface. The idea of performing polymorph screening on the template film deposited on a chip has opened up a new doorway to examine the roles of: (1) various kinds of drug carrier in the form of a template film, (2) the droplet volume of a saturated solution, and (3) the type of solvent used, in polymorphic control. Growing millimeter-sized crystals directly on the chip of template has also provided a convenient technology enabling platform for examining the crystal-template interface by solid-state characterization techniques such as ESCA.
Solubility studies were made to characterize the form of sulfathiazole controlling the rate of dissolution exhibited in previously reported dissolution rate studies of sulfathiazole coprecipitated with povidone. The aqueous solubility of the high energy form of sulfathiazole obtained using sulfathiazole--povidone coprecipitates was determined in the presence of polymer in solution. Its aqueous solubility in the absence of polymer was determined by extrapolation. The solubility value was much greater than either the supercooled melt or the crystalline forms of sulfathiazole. Stabilization of these sulfathiazole solutions supersaturated with respect to the more stable crystalline form was achieved by the addition of sufficient polymer to the solution to prevent nucleation of the crystalline form. The concentration of polymer required to prevent nucleation of the crystalline forms was much higher than the previously reported concentrations required to inhibit crystal growth of sulfathiazole. The ratio of the solubility value obtained for the coprecipitated sulfathiazole as compared with its crystalline form I was in agreement with the ratio of their dissolution rates obtained the plateau regions of the dissolution rate experiments reported previously. The extrapolated aqueous solubility values in the absence of povidone were obtained as a function of temperature and were utilized to obtain thermodynamic parameters. The difference in the heat of solution of the two forms of sulfathiazole from the slope of the van't Hoff plots of the extrapolated solubility values was 1618 cal/mole, in excellent agreement with the literature value. The free energy, enthalpy, and entropy at 27 degrees for the coprecipitated drug relative to its crystalline form I were 1125 cal/mole, 8439 cal/mole, and 24 eu, respectively, indicating the high degree of molecular randomness and lack of structure in these high energy systems. These results provide strong evidence for the presence of an amorphous state of sulfathiazole as the controlling phase of both the solubility and dissolution rate experiments involving the high energy form of sulfathiazole obtained by coprecipitation with povidone.
Laser Raman spectroscopy is used for the investigation of the drug-polymer conjugates, sulfathiazole-povidone. Specifically, Raman spectra, both in the lattice vibration and the intramolecular vibration regions, are used to characterize various polymoprhic forms of sulfathiazole. It is found that sulfathiazole exists in two unsolvated forms, untreated sulfathiazole and another form grown from propanol. The crystals grown from ethanol include varying amounts of ethanol depending on the growth condition. The nature of the povidone-sulfathiazole coprecipitates of various compositions are studied. We find no evidence of any new polymorphic form of sulfathiazole in these coprecipitates. The coprecipitates are found to consist of one of the unsolvated forms of sulfathiazole.
A sulfathiazole-resistant dihydropteroate synthase (DHPS) present in two different laboratory strains of Escherichia coli repeatedly selected for sulfathiazole resistance was mapped to folP by P1 transduction. The folP mutation in each of the strains was shown to be identical by nucleotide sequence analysis. A single C-->T transition resulted in a Pro-->Ser substitution at amino acid position 64. Replacement of the mutant folP alleles with wild-type folP significantly reduced the level of resistance to sulfathiazole but did not abolish it, indicating the presence of an additional mutation(s) that contributes to sulfathiazole resistance in the two strains. Transfer of the mutant folP allele to a wild-type background resulted in a strain with only a low level of resistance to sulfathiazole, suggesting that the presence of the resistant DHPS was not in itself sufficient to account for the overall sulfathiazole resistance in these strains of E. coli. Additional characterization of an amplified secondary resistance determinant, sur, present in one of the strains, identified it as the previously identified bicyclomycin resistance determinant bcr, a member of a family of membrane-bound multidrug resistance antiporters. An additional mutation contributing to sulfathiazole resistance, sux, has also been identified and has been shown to affect the histidine response to adenine sensitivity displayed by these purU strains.
The antimicrobial agents may undergo a change in the complex stomach particularly in the rumen as a result of microbial fermentation in ruminants. Present investigation deals with the influence of ruminal fluid probably the role of ruminal microorganisms on the degradation of sulfathiazole in vitro and its metabolism and disposition following its single intraruminal administration (100 mg/kg) in adult german black head sheep. Sulfathiazole is metabolized to N4-acetyl sulfathiazole in the rumen fluid after its in vitro incubation at different concentrations (10-60 micrograms/ml) for varying time intervals (1-6 h) at a temperature of 38 +/- 0.5 degrees C. Likewise in vivo it is significantly metabolized to its N-acetyl metabolite in the rumen after an intraruminal administration. The levels of sulfathiazole are maintained above minimum effective therapeutic concentration (40 micrograms/ml) for more than 24 h in rumen fluid. The drug is poorly absorbed into the circulation after intraruminal administration since the levels in plasma could not reach up to minimum effective therapeutic concentration at any time. The biological half-life of sulfathiazole was found to be 16.7 h following single intraruminal administration. Results of this investigation suggest that oral or intraruminal application of sulfathiazole has only local effects in the rumen fluid. A systemic treatment is not possible after this path of application.
A series of Escherichia coli strains were selected for increasing resistance to sulfathiazole. Resistance occurred in seven increments, suggesting the accumulation of several mutations that contributed to overall sulfathiazole resistance. All of the resistant strains had a sulfathiazole-resistant dihydropteroate synthase with a Pro to Ser substitution at amino acid position 64. Overproduction of the wild-type enzyme did not result in sulfathiazole resistance, however overproduction of the mutant enzyme resulted in significant resistance. Conversely, overproduction of the wild-type enzyme in a sulfathiazole-resistant background resulted in a decrease in resistance. Although the specific activity of DHPS in crude extracts was not significantly different from the wild type, the amino acid substitution resulted in an enzyme with a tenfold increase in the Km for p-aminobenzoate, and a 100-fold increase in the Ki for sulfathiazole.
Sulfathiazole and povidone were coacervated by many methods, indicating complexation of the two compounds. The coacervated complex had a higher solubility and dissolution rate than did sulfathiazole. It resisted the action of dilute acids and alkalies, suggesting a helical structure with sulfathiazole situated between two povidone chains and a hydrogen bond linking the amino groups of the sulfathiazole to the oxygen of povidone. Upon addition of precipitants for sulfathiazole, the povidone portion attempted to compensate and to solubilize the whole complex; hence, partial precipitation or coacervation occurred. A model is given to describe the dissolution profile of the different coacervate systems prepared.
The flocculation-deflocculation behavior of sulfathiazole and graphite in aqueous solutions of glycyrrhizic acid was studied by measuring the sedimentation volume and turbidity of supernates. The dispersing effect of glycyrrhizic acid on suspension of sulfathiazole showed a maximum in the pH 3-4 region, the same pH region where the zeta-potential of sulfathiazole particles showed a negative maximum. The results were explained by the variation of degrees of ionization of glycyrrhizic acid and sulfathiazole with pH. With graphite suspensions, the pH region where the dispersing effect of glycyrrhizic acid showed a maximum shifted to a higher pH compared with sulfathiazole. This result can be attributed to the fact that graphite is a nonpolar substance so the surface properties are not affected by a pH change. Hence, the adsorption of glycyrrhizic acid occurs even in a fairly high pH range.
Silver sulfathiazole shows strong antibacterial activity and good tolerance after topical application. The aim of the study was to determine the antiviral activity of silver sulfathiazole in tissue culture after incubation of drug and virus. The antiviral activity was measured after various periods of exposure and at different drug concentrations. The results obtained indicate the activity of silver sulfathiazole against Herpesvirus type 1 and type 2. This drug suppresses or completely inactivates the infectivity of virus. The antiviral effect is directly related to concentration of the drug and duration of exposure. At concentration of 10 micrograms/ml it has the highest activity after 30 minutes of exposure, however at a concentration of 20 micrograms/ml it induces a similar effect after 10 minutes. Silver sulfathiazole had antiviral activity similar to that of silver nitrate, while sulfathiazole alone was ineffective.
Plasma and urine data on sheep following administration of sulfathiazole as single intravenous and oral doses were examined. A one-compartment open model was developed to describe the pharmacokinetics of sulfathiazole in sheep. The drug was rapidly eliminated, primarily by renal excretion of unchanged sulfathiazole and metabolism to acetyl sulfathiazole, with a biological half-life of 1.3 hours. Sulfathiazole was absorbed slowly (half-life, 18 hours) and relatively completely (73%) after oral administration in solution.
Seventy-two conventionally raised pigs were challenge exposed intranasally when approximately 3.5 weeks old with yolk-grown Bordetella bronchiseptica. Twenty-four pigs acted as noninfected, nonmedicated controls. Feed containing sulfamethazine or sulfathiazole (110 mg/kg of feed) was initiated in 2 groups of 24 infected pigs each 3 days after challenge exposure and was fed continuously for 56 days. Twenty-four infected pigs were given nonmedicated feed. Challenge exposure with the B bronchiseptica resulted in nasal bordetellosis characterized by isolations of the test organism from nasal cavities of infected control pigs at greater than 90% frequency through 28 days and from at least 50% of the pigs through 56 days. Moderate turbinate atrophy developed with a 48% increase in mean turbinate space in infected control pigs at necropsy. Performance was not affected by the infection which was confined to the nasal cavity. The B bronchiseptica isolation rate decreased faster (P less than 0.01) in the sulfamethazine group than in the sulfathiazole group. By day 42, sulfamethazine-medicated pigs were negative for B bronchiseptica in nasal swab samples; whereas 8% to 17% of sulfathiazole-medicated pigs were positive from days 42 to 56. Turbinate spacing measurements averaged 11% less in the sulfamethazine group than in the sulfathiazole group.
The dynamic indentation hardness, tensile strength, bonding index, and brittle fracture index were employed to investigate the compaction properties of a plastic excipient, microcrystalline cellulose, and a brittle drug, sodium sulfathiazole, in combination with different levels of either magnesium stearate or talc. These parameters were also used to quantitate properties of various combinations of microcrystalline cellulose and sodium sulfathiazole in order to illustrate the effects of combining a plastic excipient and a brittle drug. It was shown that the tensile strength, indentation hardness, bonding index, and brittle fracture index for compacts composed of microcrystalline cellulose in combination with either talc or magnesium stearate generally decreased as the amount of talc or magnesium stearate was increased over the concentration range of 0 to 9%. Similar results were observed for admixtures of sodium sulfathiazole in combination with either talc or magnesium stearate. It was also demonstrated that the tensile strength, indentation hardness, and bonding index increased, and the brittle fracture index decreased, as the percent of microcrystalline cellulose was increased in a binary mixture of sodium sulfathiazole and microcrystalline cellulose.